The specific aim of this proposal is to test several related hypotheses each of which concerns a potential mechanism by which platelet aggregation at the site of a coronary artery stenosis may influence coronary arteriolar tone distal to it. First, we will test the hypothesis that thromboxane A2 released from aggregating platelets causes myocardial ischemia as a result of arteriolar vasospasm. Second, the hypothesis that platelet microemboli contribute to myocardial ischemia by physical occlusion of the arteriolar bed distal to the stenosis will be tested. Third, the hypothesis will be tested that adenosine and/or prostacyclin (produced in response to release of platelet derived vasoconstrictor substances) modifies the extent of arteriolar spasm which may occur in this setting. Finally, we will test the hypothesis that stimulation of platelet alpha-2 receptors by norepinephrine sensitizes platelets, thereby promoting aggregation and release of vasoactive substances (eg; thromboxane-A2 and serotonin) which in turn may contribute to an increase in coronary arteriolar tone over and above that which can be accounted for by norepinephrine's alpha-1 agonist properties alone. A closed chest, conscious porcine preparation instrumented with an artificial stenosis (74% DIA lumenal reduction) inserted in the animals' left anterior descending coronary artery will be employed for these studies. Regional myocardial blood flow will be measured by radioactive microspheres. Selective sampling of blood from the animal's anterior interventricular vein (AIV) will permit measurement of regional oxygen, lactate, and pyruvate metabolism. These parameters will be used to assess the presence and/or severity of myocardial ischemia. Determination by radioimmunoassay of thromboxane-B2 (TBX-B2) and 6-Keto-PGF-la concentrations in AIV and arterial blood will be employed to document changes in thromboxane-A2 and prostacyclin production by platelets (TBX-B2) and distal vessel walls (6-Keto-PGF-la) which may occur during platelet aggregation at the site of the stenosis. Histological examination of myocardial tissue samples also will be performed to document the extent of microvascular occlusion caused by platelet microemboli originating at the site of the stenosis. In vitro studies of platelet aggregation and release and analysis of other hematological data will be conducted in consultation with a hematologist whose area of expertise is platelet physiology. The long range objective of the proposal is to develop information which will 1) improve our understanding of the role of platelets in the pathophysiology of ischemic heart disease and 2) enhance our knowledge of mechanisms/forces influencing the local regulation of myocardial blood flow in the setting of a coronary artery stenosis.